Trial Readiness and Endpoint Assessment in LGMDR1 (TREATing-LGMDR1)

该项目的总体目标是开发可靠和有效的临床结果评估(COA)和肢体带状肌营养不良R1(LGMDR1)的生物标记物，以加速治疗开发。LGMDR1是一种常染色体隐性遗传性LGMD，其原因是肌肉结构基因CAPN3功能缺失。这种功能的丧失会导致肩部和臀部腰部肌肉的渐进性无力，从而导致渐进性残疾，包括失去行走能力或维持工作的能力。目前还没有FDA批准的LGMDR1治疗方法，这是一个巨大的未得到满足的医疗需求。LGMDR1适用于基因替代疗法；近年来，一种系统性基因疗法已被批准用于脊髓性肌萎缩症，并正在开发用于LGMDR4的基因疗法。至少有五家公司正在为LGMDR1开发基因靶向疗法或再生医学方法，这造成了治疗开发已经超过了我们为临床试验做准备的能力。这项研究的基本原理是，NorthStar对LGMD(NSAD)的动态评估是从相关疾病的广泛接受的功能评估修改而来的，需要确认为LGMDR1的主要终点。考虑到病情进展缓慢的特点，我们还预计，早期治疗试验需要一个生物标记物，如肌肉脂肪分数，以提供早期疗效信号。我们提出了以下具体目标：1)验证NSAD作为LGMDR1的主要终点；以及2)验证定量肌肉MRI作为LGMDR1的监测生物标记物。为了实现我们的目标，我们计划利用现有的LGMD临床研究网络，对我们LGMD研究网络上12个地点的100名临床受影响的、动态的和基因定义的LGMDR1患者进行为期24个月的纵向观察研究。我们假设，NSAD将服从于多个地点的培训，可靠，与患者确定的疾病影响区域相关，并对即将到来的临床试验的功率和样本量规划有用。肌肉脂肪分数可能在非甾体抗炎药变化之前显示出进展。结合起来，我们将对疾病进展进行建模，以定义NSAD的评分范围，这将定义最佳治疗试验人群。在这项研究完成时，我们将确认NSAD作为LGMDR1的主要终点；确认肌肉脂肪分数作为LGMDR1的理想生物标志物；建立临床试验特征，包括纳入/排除标准、样本量和治疗试验的临床重要差异。鉴于LGMDR1治疗开发方面的重大进展，迫切需要为这一人群开发合适的COA和生物标记物。

The overall goal of this project is to develop reliable and valid clinical outcome assessments (COAs) and biomarkers for limb girdle muscular dystrophy R1 (LGMDR1) to hasten therapeutic development. LGMDR1 is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need. LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that the NorthStar ambulatory assessment for LGMD (NSAD), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle fat fraction, is required for early phase therapeutic trials to provide an early signal of effect. We propose the following Specific Aims: 1) To validate the NSAD as a primary endpoint for LGMDR1; and 2) To validate quantitative muscle MRI as a monitoring biomarker in LGMDR1. To achieve our aims, we plan to leverage an existing LGMD Clinical Research Network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our LGMD Research Network. We hypothesize that the NSAD will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle fat fraction is likely to demonstrate progression in advance of change on the NSAD. Combined, we will model disease progression to define the range of scores on the NSAD that would define the optimal therapeutic trial population. At the completion of this study, we will have validated the NSAD as a primary endpoint for LGMDR1; validated muscle fat fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate COAs and biomarkers for this population is an urgent need.